The present invention relates in general to the field of the treatment of psoriasis and related skin disorders, and more particularly to a non-toxic topical formulation that includes antioxidants and a pharmaceutically effective amount of an herbal extract for the treatment of psoriasis and related skin ailments.
Without limiting the scope of the invention, its background is described in connection with disorders of the skin and, more particularly, to the general field of diseases that cause psoriasis, as an example.
Psoriasis is a common skin disease characterized by hyperplasia of keratinocytes resulting in thickening of the epidermis and the presence of red scaly plaques. The lesions in this chronic disease typically are subject to remissions and exacerbations. There are several patterns, of which plaque psoriasis is the most common. Guttate psoriasis, with raindrop shaped lesions scattered on the trunk and limbs, is the most frequent form in children, while pustular psoriasis is usually localized to the palms and soles. The classical inflammatory lesions vary from discrete erythematous papules and plaques covered with silvery scales, to scaly itching patches that bleed when the scales are removed. Despite a voluminous scientific literature and numerous treatment strategies, there is still no effective treatment for psoriasis that is completely without side effects.
The number of different and sometimes toxic treatments employed for amelioration of psoriasis is testimony to the resistant nature of this disease. Not only is moderate to severe psoriasis resistant to topical treatments, but because of its chronic and recurrent nature, systemic therapy or radiation is often required. The devastating nature of this disease is emphasized by the extent of the side effects that psoriasis sufferers are willing to endure to attain a remission to a disease that they know will recur sooner or later.
The present invention employs an emollient base such as moisturizing agents to promote skin re-epithelialization in order to diminish disfiguring lesions. The emollient base may include a large spectrum of suitable substances, including but not limited to creams, moisturizing creams, ointments, oils, waxes, gels, lotions, liquid suspensions or dispersions, emulsions, emulsions comprising oil in water, and the like, provided the emollient base is suitable for topical application on the skin, is substantially non-toxic and provides a suitable carrier for the non-emollient medicinal agents of the invention. A properly chosen emollient base may provide a certain amount of relief in itself for mild outbreaks of psoriasis or dermatitis.
The present invention also addresses the underlying T-cell disorder that results in an inflammatory condition. The present inventor has recognized that most, if not all, of the current therapies for psoriasis or similar T-cell mediated inflammatory skin conditions are designed to kill T-cells and to thereby ameliorate inflammation. It is possible that a major problem with the current treatments is that the therapy itself is so toxic that it may promote recurrence during healing. The toxicity of current treatments unleashes some or all of the cytokines that are associated with the promulgation of these chronic and often rebounding skin diseases.
It has been recognized by the present inventor that chronic inflammation leads to hyperproliferation and angiogenesis, and that agents that control inflammation also control angiogenesis and hyperproliferation. A prime example is corticosteroids, which are generally effective for treatment of psoriasis as well as atopic dermatitis. Corticosteroids"" side effects however, include decreased connective tissue synthesis, weakened blood vessels due to the diminished connective tissue support, bone loss, increased infection, etc. In the present invention the agent selected is capable of topical administration to have a localized effect, completely non-toxic to normal skin, and an anti-inflammatory agent. Based on the inventor""s previous experience with wound healing (Meisner, U.S. Pat. No. 4,772,591), D-glucosamine HCL was selected as one of the agents in the topical formulation for treatment of inflammatory skin diseases which, unlike the situation in wound healing, must work to oppose the activity of the T-cells. Although glucosamine has been shown to be effective in arthritis (Meisner, U.S. Pat. No. 4,647,453), inflammatory T-cells in the skin are different from those in arthritic joints. The T-cells of the skin express cutaneous lymphocyte antigen (CLA), whereas T-lymphocytes in the joint are CLA negative.
A topical skin preparation comprising glucosamine in an emollient base, therefore, is shown here to be an effective therapy for psoriasis and related skin ailments. As used herein, the term xe2x80x9cskinxe2x80x9d includes the scalp. The formulation of glucosamine in an emollient base should be suitable for topical application on human skin and may at least partially suppress, local to the area of topical application, the production of at least one cytokine that stimulates the proliferation of apoptosis-resistant keratinocytes.
Such a formulation suitable for topical application on mammalian skin may include glucosamine and extract from at least one herb that elicits at least one of the following biological effects: anti-inflammatory, antioxidant, antibacterial, antimicrobial, anti-pruritic, anti-platelet adhesion, vasodilation or keratolysis. For example, a formulation including approximately in the range of 5-25% glucosamine by weight; approximately in the range of 1-10% berberine by weight; approximately in the range of 0.5-7.5% oleuropein by weight; and approximately in the range of 47.5-93.5% emollient by weight, is shown to mitigate skin ailments local to the area of application.
The present invention also includes methods for the treatment of skin ailments. The methods include providing a formulation having approximately in the range of 5-25% glucosamine by weight; approximately in the range of 1-10% berberine by weight; approximately in the range of 0.5-7.5% oleuropein by weight; and approximately in the range of 47.5-93.5% emollient by weight; and topically applying the formulation to the affected skin. Another method includes providing a formulation having glucosamine and extract from at least one herb that elicits at least one of the following biological effects: anti-inflammatory, antioxidant, antibacterial, antimicrobial, anti-pruritic, anti-platelet adhesion, vasodilation or keratolysis; and topically applying the formulation to the affected skin. A further method for the treatment of skin ailments includes providing a formulation having glucosamine and at least one antioxidant anti-inflammatory in an emollient base and topically applying the formulation to the affected skin.
Although the mechanism of action of glucosamine is not well understood, it was shown almost 30 years ago that, in vitro, it significantly increases secretion of mucopolysaccharides by fibroblasts (N-acetylglucosamine and N-acetylgalactosamine also worked, but to a lesser degree) Karzel K. and Domenjoz R., xe2x80x9cEffects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycans metabolism of fibroblast cultures,xe2x80x9d Pharmacology 5: 337-345 (1971). This contrasts with the effects of steroids and non-steroidal anti-inflammatory drugs, which inhibit mucopolysaccharide metabolism by fibroblasts in vitro (and also appear to decrease connective tissue in vivo). Thus glucosamine, though anti-inflammatory, does not compromise normal connective tissue as do other anti-inflammatory agents. Glucosamine may work by inhibiting T-cell access to the skin as a result of the increased density of the connective tissue promoted by glucosamine. In contrast, following the use of the other agents the connective tissue tends to be compromised, leaving the skin more accessible and vulnerable to cellular infiltration. Therefore, the effect of glusosamine on T-cell induced inflammation may be explained as follows:
In normal skin aging there is a loss of connective tissue such that the dermis becomes thinner with age. Another effect of aging on the skin is the increasing incidence of skin cancer, particularly in photodamaged skin. Photodamaged skin is generally observed as having aged prematurely. Although it has been established that the main risk of non-melanoma skin cancer relates to sun exposure received before the age of 20, most skin cancers occur after age 70. This long latent period (as in other cancers with a long latent period that are associated with increasing atrophy, as occurs in the breast after menopause) may relate to the fact that although the requisite mutations for skin cancer may have been present for years (with the extent of exposure prior to age 20 the main determinant of skin cancer occurring much later in life), the mutated cells cannot expand into a region of dense connective tissue, nor can they compete with normal healthy cells in the absence of cumulative mutations. Moreover, the vascularity of aging tissues is compromised, which may partly explain the decreased immunocompetence of elderly skin. The skin of the elderly is much slower to react to antigens. The lethargic dermal immune response of the elderly suggests that the effector cells, which travel by the blood stream from the lymph nodes and must be extravasated at the site of injury, are thereby delayed.
T-cell transit in the young, on the other hand, is very efficient. Despite the dense connective tissue that must be traversed to the site of injury, T-cells in the young are able to do so quickly, perhaps due to a more accessible blood supply. Perhaps rapid transit accounts from the observation that atopic dermatitis and psoriasis occur so frequently in the young. That is, after conventional therapy following the initial insult, the connective tissue is compromised due to the corticosteroids or other therapy directed against activated T-cells, virtually inviting a recurrence of the complaint.
In contrast to the situation in the young, with increasing age, or with five or more years of immunosuppressive therapy as occurs in the case of organ transplantation (and possibly also after the toxic therapies used for psoriasis or atopic dermatitis), the density of the connective tissue is compromised. The skin is thinner and squamous cell cancer of the skin becomes more likely. It is of interest that PUVA treatments are only associated with a fourfold increase in basal cell carcinoma of the skin, no matter how many exposures have occurred, whereas the risk of SCC is dosage related. This observation with PUVA suggests that the thinning dermis (which is known to be due to UVA damage to collagen, rather than UVB) somehow promotes the development of SCC. The thinner dermis, as mentioned above, is also associated with depressed immunocompetence of the aging skin, as it rarely is seen in young skin except in the case of long-term immunosuppression. Therefore, the architecture of the skin plays a major role in immune modulation and glucosamine may play a major role in maintaining the normal architecture. Nonetheless, since psoriasis and atopic dermatitis may strike at a young age, psoriasis is clearly not related to only the thinning skin, in contrast to skin cancer and decreased skin immune response. It is postulated herein that the denser skin, with increased mucopolysaccharides promoted by glucosamine, attenuates the cytokines elaborated by the activated T-cells. Attenuation of the T-cell cytokines inhibits the inflammatory effect of the cytokines, possibly through dilution. Even in dense young skin, this may be the effect of the glucosamine: to bind nonspecifically to cytokines or to entrap the cytokines in a muccopolysaccharide xe2x80x9cnetxe2x80x9d, thereby inhibiting the inflammatory effect of the cytokines on the skin.
It has been suggested that oral glucosamine might be effective in treating psoriasis but our experiments demonstrate that topical application of glucosamine is preferred for a primary effect on the skin. The effect of glucosamine on arthritis suggests that it may be a systemic anti-inflammatory agent, but systemic anti-inflammation may not be desirable or preferred for the treatment of psoriasis and related skin ailments.
Together with agents that are observed to inhibit T-cells, or are keratolytic such as coal tar extract or salicylates such as salicylic acid, or, as demonstrated herein, with herbs having antiinflammatory, anti-bacterial, vasodilatory and/or anti-pruritic effects, a surprising synergistic response is elicited over glucosamine alone. A number of appropriate herbs that may work synergestically with glucosamine, for the present invention, are known to those of skill in the art in light of the present disclosure. Two herbs were selected that appear to work synergistically to actually cure resistant psoriatic lesions as well as resistant atopic dermatitis which has proved completely resistant to a number of standard therapies. The two herbs selected to demonstrate the required interaction are:
(1) Oleuropein: Olive leaf extract. This is a glucoside to which a great many properties have been attributed in the herbal literature. It may work in the present formulation by helping to restore the normal health of the skin by aiding in repair. Oleuropein has been called a natural antibiotic because it has been claimed to relieve symptoms of all types of infections: fungal, bacterial, viral, and parasitic. Any agent to which so many different mechanisms are attributed is generally suspect, but it has been suggested that there is an anti-viral constituent in oleuropein, calcium enolate, which is obtained after mild acid hydrolysis, and is said to work by inactivating viruses by dissolving their outer envelope. Aside from claims in the health food industry, it has long been known in Greece that during the olive harvest, the skin problems of those climbing the trees improved considerably. As a result, products containing olive leaf extract have been used in Greece for decades for treatment of psoriasis. Its efficacy in treating psoriasis, however, is generally based on hearsay, and is not documented in any medical studies. All that can be claimed with certainty is that the olive leaf extract is rich in natural antioxidants which are theoretically capable of attenuating the effects of the free radicals generated as the result of the CD8+ related cytokines. Because of the traditional use of the olive leaf extract, and its concentration of antioxidants, this chemical was selected to be used here in a formulation for treating psoriasis of the skin. Although any chemical to which so many varied curative powers are attributed is unlikely to have any specific effect, based on its composition, which should reduce inflammation to some extent due to the antioxidants, the olive leaf extract was selected as one of the constituents of the present formulation.
(2) Berberine: Oregon grapeseed extract. This herb is also said to possess antimicrobial activity, as well as being antifibrotic, anti-platelet adhesion and a natural protectant against heart disease and circulatory complaints. It has been widely used for the treatment of inflammation in Chinese herbal medicines, and has also been used to treat diarrhea in dysentary, as well as to treat non-insulin dependent diabetes mellitus. Without going exhaustively into the list of conditions for which berberine has shown a possible effect, which includes those listed above as well as for chloroquin resistant malaria and for treating ventricular tachyarrhythmias by improving left ventricular function with the production of mild systemic vasodilation. It is clear that this compound has a long track record for safety, may be anti-inflammatory, and may cause mild vasodilation that would enhance absorption of a topical preparation, and this is why Oregon grapeseed extract was included in the present formulation.
The synergistic effects of the two herbs and glucosamine results in a non-toxic highly effective treatment for psoriasis that is without the side effects observed with virtually all other therapies for moderate to severe psoriasis (mild psoriasis may be successfully treated with proper moisturizing). As illustrated by the following studies, the most common over-the-counter treatment for psoriasis, namely coal tar, may be made more effective by the use of glucosamine, even at low concentrations of coal tar. The herbal combination with glucosamine may be used to treat severe cases which berberine alone cannot.